Pro-Pigmenting Peptides

ABSTRACT

The invention is directed to the use of at least one peptide of formula: X-(Xaa1)n-Pro*-(Xaa2)m-Y (I) With: -n=0, 1 or 2; -m=0 or 1 and if m=0 then n≠0 -Xaa1 is: -An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val, V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I), Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivatives thereof; -A polar aminoacid selected from Serine (Ser, S), Threonine (Thr, T), Tyrosine (Tyr, Y), Asparagine (Asn, N), Glutamine (Gln, Q) and analogues and derivatives thereof; -or Glycine (Gly, G); When n=2 the two aminoacids Xaa1 can be the same or different; -Xaa2 is: -An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val, V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I), Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivatives thereof; -A basic aminoacid selected from Arginine (Arg, R), Lysine (Lys, K) and Histidine (His, H) and analogues and derivatives thereof; -Glycine (Gly, G) or Serine (Ser, S); -At the N terminal end of the peptide, X is selected from H, —CO—R1 and —SO2—R1; -At the C terminal end of the peptide, Y is selected from OH, OR1, NH2, NHR1 or NR1R2, R1 and R2 being independently from each other, selected from an alkyle, aryle, aralkyle, alkylaryl, alkoxy and aryloxy group, that can be linear, branched, cyclic, poly-cyclic, non-saturated, hydroxylated, carbonylated, phosphorylated and/or sulphured, with the possibility to have in said group skeleton a O, S and/or N heteroatom; -Pro* corresponding to a Proline, an analogue or derivative thereof; Excluding the peptides where X=H and Y=OH, for a non therapeutical cosmetic pro-pigmenting treatment of skin. The invention also encompasses new tripeptides of formula (I) suitable for a non therapeutical cosmetic treatment of skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 16/259,176 filed on Jan. 28, 2019, which is adivisional of U.S. patent application Ser. No. 15/361,801 filed on Nov.28, 2016, which is a divisional of U.S. patent application Ser. No.14/646,999 filed on May 22, 2015, now U.S. Pat. No. 9,534,015, whichapplication is a national phase entry under 35 U.S.C. § 371 ofInternational Application No. PCT/IB2013/060390 filed Nov. 25, 2013,published in English, which claims priority from French PatentApplication No. 1261205 filed Nov. 26, 2012, all of which are herebyincorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Nov. 24, 2013, isnamed PALPA PCT_ST25(3) and is 4.68 kilobytes in size.

TECHNICAL FIELD

The present invention relates to peptides for the treatment of skin andits appendages of mammals, humans or animals, and more particularlypeptides for a cosmetic pro-pigmenting treatment.

The invention concerns the industries of cosmetics, hygiene and personalcare, cosmeceutics and dermocosmetic products.

Peptides have an important signal function and coordinate manybiochemical processes. Therefore they became essential and promisingactive ingredients especially in the cosmetics industry where compoundsare constantly seeked that can beautify the skin and its appendages,i.e. to improve their general condition.

The present inventors are particularly interested in search of newpeptides with pro-pigmenting activity, especially at low levels, andpeptides having in addition a procollagen activity in order to proposepeptides that can have a pro-pigmenting and pro-collagen dual activity.

A pro-pigmenting active will act mainly on the stimulation of melaninsynthesis (melanogenesis), the natural pigment of the skin, body hair,eyelashes, and hair, so as to intensify the normal pigmentation of theskin and appendages without solar or UV radiations. It is themelanocytes located in the epidermis that will produce melanin from thetyrosine amino acid. Tyrosinase and then other enzymes take place toconvert tyrosine and to form melanin.

Applications include the repigmentation of cutaneous white spots andacceleration and intensification of tanning A pro-pigmenting active canalso be used for prevention and repigmentation of hair, body hair,eyelashes, eyebrows (canity treatment). Applications can be for acosmetic or dermatological purposes, preventive or curative, for examplea self-tanning treatment or a treatment for improving complexionuniformity, a treatment to strengthen the phototype of a person with alight and sun-sensitive skin, a treatment to prepare the skin before sunexposure, a treatment of white spots in particular due to a partialmelanocytic deficit.

BACKGROUND ART

Dihydroxyacetone, also known as DHA or 1,3-dihydroxy-2-propanone, is awell known pro-pigmenting active. In cosmetics, tanning agents calledTYR-OL™ and TYR-EXCEL™ proposed by Sederma and described respectively inFR2702766 and WO03/017966 based on Oleyl Tyrosine are also known.

EP2049074 describes the use of a rice protein hydrolyzate as apigmenting active. The hydrolyzate is characterized in that it comprisesa mixture of peptides in which at least 50% have a molecular weightpreferably between 300 and 3500 Da, that is to say, from 3 to about 30amino acids. Almost all naturally occurring amino acids are found in thehydrolyzate.

Besides, many peptides are disclosed for anti-age or anti-aging activityby stimulating the proteins of dermal extracellular matrix. For example,FR 2788777 patent describes PR-OH and Pal-PR-OH peptides in anti-agingcosmetic compositions.

SUMMARY OF THE INVENTION

The first object of the present invention is the directed to the use ofat least one peptide of formula:

X-(Xaa₁)_(n)-Pro*-(Xaa₂)_(m)-Y  (I)

With:

n=0, 1 or 2;

m=0 or 1 and if m=0 then n≠0

Xaa₁ is:

An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val,V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I),Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivativesthereof;

A polar aminoacid selected from Serine (Ser, S), Threonine (Thr, T),Tyrosine (Tyr, Y), Asparagine (Asn, N), Glutamine (Gln, Q) and analoguesand derivatives thereof; or

Glycine (Gly, G);

When n=2 the two aminoacids Xaa₁ can be the same or different;

Xaa₂ is:

An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val,V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I),Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivativesthereof;

A basic aminoacid selected from Arginine (Arg, R), Lysine (Lys, K) andHistidine (His, H) and analogues and derivatives thereof;

Glycine (Gly, G) or Serine (Ser, S);

At the N terminal end of the peptide, X is selected from H, —CO—R₁ and—SO2—R₁;

At the C terminal end of the peptide, Y is selected from OH, OR₁, NH₂,NHR₁ or NR₁R₂,

R₁ and R₂ being independently from each other, selected from an alkyle,aryle, aralkyle, alkylaryl, alkoxy and aryloxy group, that can belinear, branched, cyclic, poly-cyclic, non-saturated, hydroxylated,carbonylated, phosphorylated and/or sulphured, with the possibility tohave in said group skeleton a O, S and/or N heteroatom;

Pro* corresponding to a Proline, an analogue or derivative thereof;

Excluding the peptides where X=H and Y=OH,

For a non therapeutical cosmetic pro-pigmenting treatment of skin.

The inventors have shown that such peptides have a cosmetic activity andcan be used individually or in combination to improve the appearance andgeneral condition of the skin and its appendages, and in particular forthe treatment and/or prevention of signs of aging and/or imperfectionsof skin and its appendages, in particular thanks to a pro-pigmentingactivity.

More particularly, according to the invention a pro-pigmenting cosmeticuse comprises the repigmentation of cutaneous white spots andacceleration and intensification of tanning, prevention andrepigmentation of hair, body hair, eyelashes, eyebrows (canitytreatment), self-tanning treatment or a treatment for improvingcomplexion uniformity, a treatment to strengthen the phototype of aperson with a light and sun-sensitive skin, a treatment to prepare theskin before sun exposure or a treatment of white spots in particular dueto a partial melanocytic deficit.

The peptides of the invention advantageously have a pro-pigmentingactivity even at in low ppm content, around 3 ppm for some of them, andin any case below 20 ppm. The presence of a proline (orpyrrolidine-2-carboxylic acid, the following formula II) is an essentialelement of the invention. It induces a strong geometrical constraint onthe peptide skeleton. This configuration forces a “angled” shape (or asa hook) to the peptide. If the proline is substituted by a more flexibleamino acid such as a glycine the pro-pigmenting activity disappears.

The following developed formula III of the peptide Pal-LPA-OH accordingto the invention illustrates as an example this angled structure:

The present invention also encompasses proline derivatives or analoguesthat are also capable to induce such a bend. These derivatives oranalogues are either:

1) Derived from rings of different size (e.g. 4 or 6 bonds);

2) Derived from the change in the relative position (α or β) of the acidfunction (COOH) with respect to the nitrogen-containing cycle.

3) Derived from substitutions on the cycle changing its overall sizeand/or its polarity.

4) Derived from the combination of the above items.

The peptides can be represented by the following general formula IV:

In either position

The present invention preferably provides the following analoguespresented in the following Table 1 with a nitrogen in the ring as theproline (5 atoms cycle and COOH in α):

Compound name Chemical structure azetidine-2-carboxylic acid 4 atomscycle and COOH in α β-proline (or pyrrolidine-3-carboxylic acid) 5 atomscycle and COOH in β pipecolic acid 6 atoms cycle and COOH in α nipecoticacid 6 atoms cycle and COOH in β thio-proline (orthiazolidine-4-carboxylic 5 atoms cycle and COOH in acid) α + S inposition 4 4-hydroxy-proline 5 atoms cycle and COOH in α + OH inposition 4 3,4-dehydro-proline 5 atoms cycle and COOH in α +insaturation in 3-4

Other compounds resulting from the substitution of proline with a Rgroup are also possible. Non-limiting examples are given in Table 2:

R group Position piperidin-4-y1 1 on nitrogen phenyl; dimethyl 3 phenyl;OH; NH₂; F; F₂; CF₃; benzyl; 4 cyclohexyl; oxo; bromobenzyl; SH; phenoxyphenyl; dimethyl; oxo 5 phenyl, cyclohexyl 4 + 5

Proline can also be replaced by substituted analogues having a 6 linkcycle as the examples given in following Table 3:

Compound name Chemical structure 3-carboxy-morpholine 6 atoms cycleoxygenated + COOH in position 3 2-carboxy-morpholine 6 atoms cycleoxygenated + COOH in position 2 Tic (or1,2,3,4-tétrahydroisoquinoline-3- 6 atoms cycle oxygenated + carboxylicacid) and its hydroxylated COOH in position 2 on this derivative cycle +phenyl in position 4 + 5 Tiq (or 1,2,3,4-tetrahydroisoquinoline-1- 6atom cycle + COOH carboxylic acid) in position 6 sur on this cycle +indole in position 4 + 5

According to the invention, preferably in formula I:

Pro* is Proline, a natural amino acid; and/or

Xaa₁ is selected from Alanine (Ala, A), Methionine (Met, M), Leucine(Leu, L), Isoleucine (Ile, I), Proline (Pro, P), Serine (Ser, S),Tyrosine (Tyr, Y) and Glutamine (Gln, Q); and more preferably selectedfrom Leucine (Leu, L), Proline (Pro, P), Serine (Ser, S) and Glutamine(Gln, Q), and/or

Xaa₂ is selected from Alanine (Ala, A), Arginine (Arg, R), Methionine(Met, M), Glycine (Gly, G) and Serine (Ser, S).

As shown in examples given below in the detailed description, betterresults in pro-pigmentation can be obtained with these preferredamino-acids.

According to other features of the invention, preferably n=1 and m=0, orn=0 and m=1, in order to provide dipeptides, or n=2 and m=0, or n=1 andm=1, in order to provide tripeptides, dipeptides and tripeptides beingeasier and less expensive to synthesize.

Thus, proline based dipeptides covered by the invention can be selectedfrom:

If n=0 and m=1: the general formula is then:

X-Pro-Xaa₂-Y  (formula V):

X-PA-Y, X-PV-Y, X-PM-Y, X-PL-Y, X-PI-Y, X-PF-Y, X-PP-Y, X-PR-Y, X-PK-Y,X-PH-Y, X-PG-Y and X-PS-Y, and more preferably X-PA-Y, X-PR-Y, X-PM-Y,X-PG-Y and X-PS-Y, according to the above mentioned preferred Xaa₂ aminoacids.

If n=1 and m=0: the general formula is then:

X-Xaa₁-Pro-Y  (formula VI):

X-AP-Y, X-VP-Y, X-MP-Y, X-LP-Y, X-IP-Y, X-FP-Y, X-PP-Y, X-SP-Y, X-TP-Y,X-YP-Y, X-NP-Y, X-QP-Y and X-GP-Y, and preferably X-AP-Y, X-MP-Y,X-LP-Y, X-IP-Y, X-PP-Y, X-SP-Y, X-YP-Y and X-QP-Y, and more preferablyX-LP-Y, X-PP-Y, X-SP-Y and X-QP-Y, according to the above mentionedpreferred Xaa₁ amino acids.

The preferred dipeptides according to the invention are thus the X-PA-Y,X-PR-Y, X-PM-Y, X-PG-Y, X-PS-Y, X-LP-Y, X-PP-Y, X-SP-Y and X-QP-Y.

Tripeptides covered according to the invention based on proline can inturn be selected from:

If n=1 and m=1, the general formula is then:

X-Xaa₁-Pro-Xaa₂-Y  (formula VII):

Preferably, according to the above mentioned preferred amino-acids, thetripeptides of formula VII are selected from: X-APA-Y, X-APR-Y, X-APM-Y,X-APG-Y, X-APS-Y, X-MPA-Y, X-MPR-Y, X-MPM-Y, X-MPG-Y, X-MPS-Y, X-LPA-Y,X-LPR-Y, X-LPM-Y, X-LPG-Y, X-LPS-Y, X-IPA-Y, X-IPR-Y, X-IPM-Y, X-IPG-Y,X-IPS-Y, X-PPA-Y, X-PPR-Y, X-PPM-Y, X-PPG-Y, X-PPS-Y, X-SPA-Y, X-SPR-Y,X-SPM-Y, X-SPG-Y, X-SPS-Y, X-YPA-Y, X-YPR-Y, X-YPM-Y, X-YPG-Y, X-YPS-Y,X-QPA-Y, X-QPR-Y, X-QPM-Y, X-QPG-Y, X-QPS-Y, X-GPA-Y, X-GPR-Y, X-GPM-Y,X-GPG-Y and X-GPS-Y.

Even more preferably the tripeptides of formula VII are selected from:X-LPA-Y, X-LPR-Y, X-LPM-Y, X-LPG-Y, X-LPS-Y, X-PPA-Y, X-PPR-Y, X-PPM-Y,X-PPG-Y, X-PPS-Y, X-SPA-Y, X-SPR-Y, X-SPM-Y, X-SPG-Y, X-SPS-Y, X-QPA-Y,X-QPR-Y, X-QPM-Y, X-QPG-Y and X-QPS-Y.

As preferred examples of tetrapeptides, responding to the formulaX-Xaa₁-Xaa1-P-Xaa₂-Y (formula VIII) with n=2 and m=1, the following canbe cited X-AQPR-Y (SEQ ID NO: 1) and X-AQPK-Y (SEQ ID NO: 2).

The inventors have shown that the peptides according to the inventionhave a pro-pigmenting activity as well as for some of them an additionalstimulatory activity of collagen synthesis, advantageously providing anactive with a dual activity, pro-pigmenting and pro-collagen, activityparticularly interesting in particular for a anti-aging goal (treatmentof spots and wrinkles with the same active).

This is the case in particular for the following peptides X-SPR-Y,X-PPR-Y, X-QPA-Y, X-LPA-Y, X-SPA-Y, X-PM-Y, and X-PA-Y, as can be seenin the detailed examples given below.

Advantageously also, some of the peptides present a keratinocytedifferentiation property which allows to consider an additional activityat the epiderm level (moisturizing, strengthening the skin barrier).This activity also complements a global anti-aging activity.

This is the case in particular for the following peptides X-LPR-Y,X-SPR-Y, X-PA-Y and X-LPA-Y, as can be seen also in the detailedexamples.

As a second subject matter the present invention proposes the followingnew peptides, suitable for a cosmetic treatment in particular apro-pigmenting treatment, of formula:

X-(Xaa₁)-Pro*-(Xaa₂)_(m)-Y  (I)

With:

n=1 or 2;

m=1;

Xaa₁ is:

An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val,V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I),Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivativesthereof;

A polar aminoacid selected from Serine (Ser, S), Threonine (Thr, T),Tyrosine (Tyr, Y), Asparagine (Asn, N), Glutamine (Gln, Q) and analoguesand derivatives thereof; or

Glycine (Gly, G);

When n=2 the two aminoacids Xaa₁ can be the same or different;

Xaa₂ is:

An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val,V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I),Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivativesthereof;

A basic aminoacid selected from Arginine (Arg, R), Lysine (Lys, K) andHistidine (His, H) and analogues and derivatives thereof; or

Glycine (Gly, G) or Serine (Ser, S);

At the N terminal end of the peptide, X is selected from H, —CO—R₁ and—SO₂—R₁;

At the C terminal end of the peptide, Y is selected from OH, OR₁, NH₂,NHR₁ or NR₁R₂,

R₁ and R₂ being independently from each other, selected from an alkyle,aryle, aralkyle, alkylaryl, alkoxy and aryloxy group, that can belinear, branched, cyclic, poly-cyclic, non-saturated, hydroxylated,carbonylated, phosphorylated and/or sulphured, with the possibility tohave in said group skeleton a O, S and/or N heteroatom;

Pro* corresponding to a Proline, an analogue or derivative thereof;

Excluding the peptides where X=H and Y=OH.

According to the invention, as mentioned above, preferably in formula I:

Pro* is Proline, a natural amino acid; and/or

Xaa₁ is selected from Alanine (Ala, A), Methionine (Met, M), Leucine(Leu, L), Isoleucine (Ile, I), Proline (Pro, P), Serine (Ser, S),Tyrosine (Tyr, Y) and Glutamine (Gln, Q); and more preferably selectedfrom Leucine (Leu, L), Proline (Pro, P), Serine (Ser, S) and Glutamine(Gln, Q), and/or

Xaa₂ is selected from Alanine (Ala, A), Arginine (Arg, R), Methionine(Met, M), Glycine (Gly, G) and Serine (Ser, S).

As mentioned above also, preferably the new tri-peptides according tothe invention are selected from X-APA-Y, X-APR-Y, X-APM-Y, X-APG-Y,X-APS-Y, X-MPA-Y, X-MPR-Y, X-MPM-Y, X-MPG-Y, X-MPS-Y, X-LPA-Y, X-LPR-Y,X-LPM-Y, X-LPG-Y, X-LPS-Y, X-IPA-Y, X-IPR-Y, X-IPM-Y, X-IPG-Y, X-IPS-Y,X-PPA-Y, X-PPR-Y, X-PPM-Y, X-PPG-Y, X-PPS-Y, X-SPA-Y, X-SPR-Y, X-SPM-Y,X-SPG-Y, X-SPS-Y, X-YPA-Y, X-YPR-Y, X-YPM-Y, X-YPG-Y, X-YPS-Y, X-QPA-Y,X-QPR-Y, X-QPM-Y, X-QPG-Y, X-QPS-Y, X-GPA-Y, X-GPR-Y, X-GPM-Y, X-GPG-Yand X-GPS-Y, and more preferably X-LPA-Y, X-LPR-Y, X-LPM-Y, X-LPG-Y,X-LPS-Y, X-PPA-Y, X-PPR-Y, X-PPM-Y, X-PPG-Y, X-PPS-Y, X-SPA-Y, X-SPR-Y,X-SPM-Y, X-SPG-Y, X-SPS-Y, X-QPA-Y, X-QPR-Y, X-QPM-Y, X-QPG-Y andX-QPS-Y, and even more preferably X-SPR-Y, X-PPR-Y, X-QPA-Y, X-LPA-Y andX-SPA-Y when a dual activity pro-pigmenting and pro-collagen is seeked.

The preferred tetrapeptides according to the invention are X-AQPR-Y (SEQID NO: 1) and X-AQPK-Y (SEQ ID NO: 2).

According to other preferred features of the invention:

R₁ and/or R₂ is an alkyl chain having 1 to 24 carbon atoms, preferably 3to 24 carbon atoms; and/or

X is a CO—R₁ acyl group and Y is selected from OH, OMe, OEt and NH₂,preferably OH; X is preferably selected from octanoyle (C₈), decanoyle(C₁₀), lauroyl (C₁₂), myristoyle (C₁₄), palmitoyle (C₁₆), stearoyle(C₁₈), biotinoyle, elaidoyle, oleoyle and lipoyle; more preferablyselected from lauroyle (C₁₂), myristoyle (C₁₄) and palmitoyle (C₁₆);and/or

Y is OH and X is selected from palmitoyle (C₁₆), myristoyle (C₁₄) andlauroyle (C₁₂).

Preferably the peptide for the pro-pigmenting use according to theinvention is selected from Pal-QPR-OH, Pal-YPR-OH, Pal-SPR-OH,Pal-LPR-OH, Myr-LPR-OH, Lau-LPR-OH, Pal-APR-OH, Pal-PPR-OH, Pal-QPK-NH₂,Pal-QPH-OH, Pal-QPM-OH, Pal-QPA-OH, Pal-LPA-OH, Pal-SPA-OH, Pal-PPA-OH,Myr-SPA-OH, Pal-LPM-OH, Pal-IPM-OH, Pal-MPL-OH, Pal-PR-OH, Myr-PR-OH,Pal-PM-OH, Pal-PP-OH, Pal-PG-OH, Pal-PS-OH, Pal-PA-OH, Pal-AP-OH andPal-GP-OH.

Preferably for a dual activity pro-pigmenting and pro-collagen, thepeptide is preferably selected from Pal-SPR-OH, Pal-PPR-OH, Pal-QPA-OH,Pal-LPA-OH, Myr-SPA-OH, Pal-PM-OH, and Pal-PA-OH.

The peptides of the invention may be optically pure, or consist of D orL isomers or a mixture thereof. The L isomers that are those found innature may be preferred.

The peptides may be in the form of salts, especially hydrochloride salt.

In addition, the peptides of the invention may consist of a largerpeptide fragment, containing more amino acids than the di-, tri-ortetra-peptide active “heart” of the invention.

The present invention also encompasses derivatives (with modificationand/or addition of a chemical function but without change in the carbonskeleton) and analogues (with modification and/or addition of a chemicalfunctional but with an additional change in the carbon skeleton),complex with other species such as a metal ion (eg copper, zinc,manganese, magnesium, and others).

Example of analogues of hydrophobic amino-acids for Xaa₁ and/or Xaa₂ canbe for example for alananine the beta-alanine, alpha or gammaaminobutyric acid or 5-amino-valeric acid, as well as their superiorhomologues, the preferred one being the beta-alanine for alanine.

The present invention also provides a composition, especially topical,comprising at least one peptide according to the invention or accordingto the use of the invention in a physiologically acceptable medium.According to the excipient and the dosage of peptide, this compositionwill constitute for example a concentrated active ingredient or a lessconcentrated final composition directly for the patient.

“Physiologically acceptable medium” means according to the presentinvention, without limitation, an aqueous or hydroalcoholic solution, awater-in-oil emulsion, an oil-in-water emulsion, a micro-emulsion, anaqueous gel, an anhydrous gel, a serum, a dispersion of vesicles, or apowder.

“Physiologically acceptable” means that the compositions are suitablefor topical or transdermal use, in contact with mucous membranes,appendages (nails, hair and body hair), scalp and skin of mammals,particularly human, compositions which may be ingested or injected intothe skin, without risk of toxicity, incompatibility, instability,allergic response, and others.

This “physiologically acceptable medium” forms what is commonly calledthe excipient of the composition.

The peptides of the invention may be dissolved in a lipophilic orhydrophilic matrix with a solubilizer if necessary according to futureuse.

The peptide(s) may be combined with other active ingredients ineffective concentrations to act synergistically or to reinforce and toachieve the desired effects described in the invention, such as thefollowing ingredients: radiation filters, including UVA UVB,moisturizing, calming, muscle relaxant, slimming, restructuring,firming, re-fillling, firming, acting on the microcirculation, acting oninflammation, on free radicals, vitamins, anti-wrinkle agents, etc.

The peptide composition according to the invention can be applied to theface, body, neck, scalp, hair, eyelashes, body hair, in any form orvehicules known from the ones skilled in the art, in particular in theform of solution, dispersion, emulsion, paste or powder, individually oras a premix in vectors suc as macrocapsules, microcapsules ornanocapsules, macrospheres, microspheres or nanospheres, liposomes,oleosomes or chylomicrons, macroparticules, microparticules ornanoparticules, macrosponges, microsponges or nanosponges,microemulsions or nanoemulsions, or adsorbed on organic polymer powders,talcs, bentonites, spores or exines and other inorganic or organicsupports.

In particular in cosmetics, applications can be proposed including inthe ranges of skin care for face, body, hair and body hair andmakeup-care lines, including eyebrows and eyelashes.

The peptides according to the present invention may in general be usedin any form whatsoever, in a form bound to or incorporated in orabsorbed in or adsorbed on macro-, micro-, and nanoparticles, or macro-,micro-, and nanocapsules, for the treatment of textiles, natural orsynthetic fibers, wools, and any materials that may be used for clothingor underwear for day or night intended to come into contact with theskin, handkerchiefs or cloths, to exert their cosmetic or therapeuticaleffect via this skin/textile contact and to permit continuous topicaldelivery.

The CTFA International cosmetic ingredient dictionary & handbook (13thEd. 2010) (published by the Cosmetic, Toiletry, and FragranceCombination, Inc., Washington, D.C.) describes a non-limited widevariety of cosmetic and pharmaceutical ingredients conventionally usedin the skin care industry that can be used as additionalingredients/compounds in the compositions of the present invention.

Further skin care and hair care active ingredients that are particularlyuseful can be found in Sederma's commercial literature and on thewebsite www.sederma.fr.

The following commercial actives can also be mentioned, as examples:betain, glycerol, Actimoist Bio 2™ (Active organics), AquaCacteen™(Mibelle AG Cosmetics), Aquaphyline™ (Silab), AquaregulK™ (Solabia),Carciline™ (Greentech), Codiavelane™ (Biotech Marine), Dermaflux™ (ArchChemicals, Inc), Hydra'Flow™ (Sochibo), Hydromoist L™ (Symrise),RenovHyal™ (Soliance), Seamoss™ (Biotech Marine), Argireline™ (tradename of the acetyl hexapeptide-3 of Lipotec), spilanthol or an extractof Acmella oleracea known under the name Gatuline Expression™, anextract of Boswellia serrata known under the name Boswellin™, DeepalinePVB™ (Seppic), Syn-AKE™ (Pentapharm), Ameliox™ Bioxilift™ (Silab),PhytoCellTec™Argan (Mibelle), Papilactyl D™ (Silab), Preventhelia™(Lipotec), Subliskin™ (Sederma), Venuceane™ (Sederma), Moist 24™(Sederma), Vegesome Moist 24™ (Sederma), Essenskin™ (Sederma), Juvinity™(Sederma), Revidrate™ (Sederma), Resistem™ (Sederma), Chronodyn™(Sederma), Kombuchka™ (Sederma), Chromocare™ (Sederma), Calmosensine™(Sederma), Glycokin factor S™ (Sederma), Biobustyl™ (Sederma), Idealift™(Sederma), Ceramide 2™, Ceramide A2™ et Ceramide HO3™ (Sederma),Legance™ (Sederma), Intenslim™ (Sederma), Prodizia™ (Sederma),Beautifeye™ (Sederma), or mixtures thereof.

Among the plant extracts which can be combined with the peptide of theinvention, there may more particularly be mentioned extracts of Ivy, inparticular English Ivy (Hedera helix), of Bupleurum chinensis, ofBupleurum falcatum, of arnica (Arnica nontana L), of rosemary(Rosmarinus officinalis N), of marigold (Calendula officinalis), of sage(Salvia officinalis L), of ginseng (Panax ginseng), of ginko biloba, ofSt.-John's-Wort (Hyperycum perforatum), of butcher's-broom (Ruscusaculeatus L), of European meadowsweet (Filipendula ulmaria L), ofbig-flowered Jarva tea (Orthosiphon stamincus benth), of algae (Fucusvesiculosus), of birch (Betula alba), of green tea, of cola nuts (Colanipida), of horse-chestnut, of bamboo, of Centella asiatica, of heather,of fucus, of willow, of mouse-ear, of escine, of cangzhu, ofchrysanthellum indicum, of the plants of the Armeniacea genus,Atractylodis platicodon, Sinnomenum, Pharbitidis, Flemingia, of Coleussuch as C. forskohlii, C. blumei, C. esquirolii, C. scutellaroides, C.xanthantus and C. barbatus, such as the extract of root of Coleusbarbatus, extracts of Ballote, of Guioa, of Davallia, of Terminalia, ofBarringtonia, of Trema, of antirobia, cecropia, argania, dioscoreae suchas Dioscorea opposita or Mexican, extracts of Ammi visnaga, ofSiegesbeckia, in particular Siegesbeckia orientalis, vegetable extractsof the family of Ericaceae, in particular bilberry extracts (Vacciniumangustifollium) or Arctostaphylos uva ursi, Aloe vera, plant containingsterols (e.g., phytosterol), Manjistha (extracted from plants of thegenus Rubia, particularly Rubia cordifolia), and Guggal (extracted fromplants of the genus Commiphora, particularly Commiphora mukul), kolaextract, chamomile, red clover extract, Piper methysticum extract (KavaKava™ from SEDERMA), Bacopa monieri extract (Bacocalmine™ from SEDERMA)and sea whip extract, extracts of Glycyrrhiza glabra, of mulberry, ofmelaleuca (tea tree), of Larrea divaricata, of Rabdosia rubescens, ofEuglena gracilis, of Fibraurea recisa hirudinea, of Chaparral sorghum,of sun flower extract, of Enantia chlorantha, of Mitracarpe ofSpermacocea genus, of Buchu barosma, of Lawsonia inermis L., ofAdiantium capillus-veneris L., of Chelidonium majus, of Luffacylindrica, of Japanese Mandarin (Citrus reticulata blanco var. unshiu),of Camelia sinensis, of Imperata cylindrica, of Glaucium flavum, ofCupressus sempervirens, of Polygonatum multiflorum, of Loveyly hemsleya,of Sambucus nigra, of Phaseolus lunatus, of Centaurium, of Macrocystispyrifera, of Turnera diffusa, of Anemarrhena asphodeloides, of Portulacapilosa, of Humulus lupulus, of Coffea arabica, of Ilex paraguariensis,of Globularia cordifolia, of Albizzia julibrissin, Oxydendron arboretumor of Zingimber zerumbet smith.

The compositions of the present invention may include other peptides,including, without limitation, the di-, tri-, tetra-, penta-andhexapeptides and their derivatives. According to a particularembodiment, the concentration of the additional peptide, in thecomposition, ranges from 1×10⁻⁷% and 20%, preferably from 1×10⁻⁶% and10%, preferably between 1×10⁻⁵% and 5%, by weight.

According to the present invention, the term “peptide” refers topeptides containing 10 amino acids or less, their derivatives, isomersand complexes with other species such as a metal ion (e.g. copper, zinc,manganese, magnesium, and others). The term “peptides” refers to bothnatural peptides and synthetic peptides. It also refers to compositionsthat contain peptides which are found in nature, and/or are commerciallyavailable.

Suitable dipeptides for use within the scope of the present inventioninclude but are not limited to carnosine (beta-AH), YR, VW, NF, DF, KT,KC, CK, KP, KK or TT. Non limitative suitable tripeptides for use hereininclude, but are not limited to RKR, HGG, GHK, GKH, GGH, GHG, KFK, KPK,KMOK, KMO₂K or KAvaK. Non limitative suitable tetrapeptides for useherein include but are not limited to RSRK (SEQ ID NO: 3), GQPR (SEQ IDNO: 4) or KTFK (SEQ ID NO: 5). Non limitative suitable pentapeptidesinclude, but are not limited to KTTKS (SEQ ID NO: 6) and hexapeptidesinclude but are not limited to GKTTKS (SEQ ID NO: 7) and VGVAPG (SEQ IDNO: 8).

Other suitable peptides for use in the context of the present inventioninclude, but are not limited to: lipophilic derivatives of peptides,preferably palmitoyl derivatives, and metal complexes as aforementioned(e.g. copper complex of the tripeptide HGG). Preferred dipeptidederivatives include N-Palmitoyl-beta-Ala-His,N-Acetyl-Tyr-Arg-hexadecylester (Calmosensine™, Idealift™ from Sederma).Preferred tripeptide derivatives include in particular theN-Palmitoyl-Gly-Lys-His, and Pal-Gly-His-Ly, (Pal-GKH and Pal-GHK fromSederma), the copper derivative of HGG (Lamin™ from Sigma), Lipospondin(N-Elaidoyl-KFK) and its analogues of conservative substitution,N-Acetyl-RKR-NH₂ (Peptide CK+), N-Biot-GHK (from Sederma), Pal-KMO₂K(Sederma) and derivatives thereof. Suitable tetrapeptide derivatives foruse according to the present invention include, but are not limited to,N-palmitoyl-GQPR (SEQ ID NO: 9) (from Sederma), Ela-KTFK (SEQ ID NO:10). Suitable pentapeptide derivatives for use herein include, but arenot limited to, N-Palmitoyl-KTTKS (SEQ ID NO: 11) (available asMatrixyl™ from Sederma), N-Palmitoyl-Tyr-Gly-Gly-Phe-X (SEQ ID NO: 12)with X Met or Leu or mixtures thereof. Suitable hexapeptide derivativesfor use herein include, but are not limited to, N-Palmitoyl-VGVAPG (SEQID NO: 13), Pal-GKTTKS (SEQ ID NO: 14) and derivatives thereof. Themixture of Pal-GHK and Pal-GQPR (SEQ ID NO: 9) (Matrixyl™ 3000, Sederma)can also be mentioned.

The preferred compositions commercially available containing atripeptide or a derivative include Biopeptide-CL™, Maxilip™, Biobustyl™,Procapil™ and Matrixyl™synthe'6™ of Sederma. The compositionscommercially available preferred sources of tetrapeptides includeRigin™, Eyeliss™, Matrixyl™ Reloaded and Matrixyl 3000™ which containbetween 50 and 500 ppm of Palmitoyl-GQPR (SEQ ID NO: 9) and carrier,proposed by Sederma.

The following marketed peptides can be mentioned as well as additionalactive ingredients: Vialox™, Syn-ake™ or Syn-Coll™ (Pentapharm),Hydroxyprolisilane CN™ (Exsymol), Argireline™, Leuphasyl™, Aldenine™,Trylgen™, Eyeseryl™, Serilesine™ or Decorinyl™ (Lipotec), Collaxyl™ orQuintescine™ (Vincience), BONT-L-Peptide™ (lnfinitec Activos),Cytokinol™LS (Laboratoires Serobiologiques/Cognis), Kollaren™ IP2000™ orMeliprene™ (lnstitut Europeen de Biologie Cellulaire), Neutrazen™(Innovations), ECM-Protect™ (Atrium Innovations), Timp-Peptide™ or ECMModuline™ (lnfinitec Activos).

The present invention also provides a topical cosmetic, cosmeceutical ordermopharmaceutical treatment method to improve the appearance andcondition of the skin and its appendages, comprising the topicalapplication to the skin of a subject in need thereof of an effectiveamount of a peptide according to the invention or a compositionaccording to the invention comprising said peptide as recited above.

“Topical treatment” or “topical use” means an application that isintended to act where it is applied: skin, mucous, appendages.

The peptide or composition according to the invention can be appliedlocally applied to targeted areas.

The “effective” amount depends on various factors, such as the age, thecondition of the patient, the severity of the disorder or disease andthe administration mode. An effective amount means a non-toxic amountenough to achieve the desired effect.

In a cosmetic composition according to the invention, the peptides to bepresent in an effective amount, are generally present in an amountranging from 0.000001% and 15% based on the total weight of thecomposition, preferably between 0.0001% and 5% depending on thedestination of the composition and the more or less pronounced derisedeffect. The peptides may be present in the compositions according to theinvention in varying relative proportions, in equivalent amounts orotherwise in different proportions.

All percentages and ratios used herein are by weight of the totalcomposition and all measurements are made at 25° C. unless it isotherwise specified.

For example, for a face cosmetic treatment, the SCCCS'S (ScientificCommittee on Consumer Safety) Notes of Guidance for the testing ofcosmetic substances and their safety evaluation (8^(th) Revision, 11Dec. 2012) has set a standard amount for applying a cream of 2.72mg/cm²/day/person and for a body lotion of 0.5 mg/cm²/day/person.

According to other specific features, the cosmetic treatment methodaccording to the invention can be combined with one or more othertreatment methods targeting the skin such as lumino-therapy, heat oraromatherapy treatments.

According to the invention, devices with several compartments or kitsmay be proposed to apply the method described above which may includefor example and non-restrictively, a first compartment containing acomposition comprising the peptide of the invention, and in a secondcompartment an excipient and/or an additional active, the compositionscontained in the said first and second compartments in this case beingconsidered to be a combination composition for simultaneous, separate orstepwise use in time, particularly in one of the treatment methodsrecited above.

The treatment method according to the invention is particularly suitablefor:

A pro-pigmenting treatment;

To prevent and/or treat the loss of pigmentation of the skin and itsappendages (body hair, eyelashes, eyebrows or hair), especially fortreating cutaneous white spots and/or canities;

To improve cutaneous phototype of a person with a white and/or sensitiveskin in particular to prepare the skin and its appendages to sunexposure;

A tanning, tanning accelerating treatment;

To prevent and/or treat the default of complexion homogeneity;

For preventing and/or treating the loss of collagen in the skinextracellular matrix or for stimulating the synthesis of collagen toobtain a volumizing effect;

For preventing and/or treating the loss of skin hydration by improvingthe skin barrier and/or;

For an anti-aging treatment, in partircular anti-wrinkles and finelines, moisturizing and for unifying.

Other applications can be envisaged for example slimming, loss ofelasticity, detoxification, anti-glycation, anti-free radical,anti-oxidants, tensor, anti-fatigue, anti-dark circles and/or under eyerings, calming, firming, hair and body hair growth, complexion etc. fora preventive or curative action.

DETAILED DESCRIPTION

The following examples describe and illustrate some aspects of theinvention. They should not be seen as limiting the disclosure, as theyonly provide useful information for understanding and implementation.

A) Example of synthesis of the peptide according to the invention, thePal-PA-OH:

The Pal-PA-OH peptide is prepared by peptidic synthesis. Proline isacylated on its amine function with an activated derivative of palmiticacid (palmitoyl chloride for example) in the presence of a base toobtain the palmitoyl-proline. The latter is then activated on itsterminal acid function with a coupling agent (DCC(diclyclohexylcarbodiimide)/NHS (N-hydroxysuccinimide) or HBTU(2-1H-enzotriazole- 1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate)/HOBT (1-hydroxybenzotriazole)) to react with thealanine. After precipitation, washing and drying, thepalmitoyl-prolyl-alanine product is obtained in a solid form.

B) Preparation of a composition according to the invention comprisingthe Pal-PA-OH peptide of example A).

Starting Products:

The Pal-PA-OH pur peptide, synthetized according the synthesis methodexplained above;

Excipient: a mixture of fatty esters, selected to form an oil matrix,for example for forming a water-free composition for the formulation ofsubsequent cosmetic water-free end-compositions.

Protocol:

the Pal-PA-OH peptide is mixed with the excipient and placed undergentle stirring and heating until complete dissolution and clarity.

C) In vitro evaluations

The peptides of the invention have a number of remarkable effectspresented below. Peptides prepared according to A) above and dissolvedin a fatty excipient to form compositions according to Example B) werein vitro tested and demonstrated a pro-pigmenting activity and for someof them an additionnal pro-collagen activity, that are presented below.Comparative tests are also presented below.

1. Pro-pigmenting Activity (Melanogenesis)

a) Test on B16 Cells

Mouse melanoma (B16 cells) were grown in their maintenance medium (DMEMc+10% FCS) in the presence of the products and positive references fromthe literature for 48 hours. At the end of the contact, the melaninswere extracted from the cells and assayed by spectrophotometry. Inparallel, the residual tyrosinase activity (dopa oxidase) of the cellswas assayed by spectrophotometry in the presence of one of thesubstrates of the enzyme: the L-DOPA. An estimate of the viability ofthe cells was also performed at the end of culture using a protein assayby the BCA method.

b) Test on Human Melanocytes

Normal human melanocytes (HEMn cells) were seeded in their maintenancemedium then brought into contact with the products and the positivecontrols (literature references) in a test medium suitable for theculture of melanocytes for 10 days. At the end of the contact, themelanin are extracted from cells and assayed by spectrophotometry. Inparallel, the residual tyrosinase activity (dopa oxidase) of the cellswas assayed by spectrophotometry in the presence of one of thesubstrates of the enzyme: the L-DOPA. An estimate of the viability ofthe cells was also performed at the end of culture using a protein assayby the BCA method.

c) Results on Pro-Pigmentation

Peptides On B16 cells On human melanocytes IBMX(isobutyl-methyl-xanthine) +++ +++ Pal-AQPR-OH (SEQ ID NO: 15) +++Pal-AQPK-OH (SEQ ID NO: 16) +++ Pal-QPR-OH ++ Pal-YPR-OH ++++ ++Pal-SPR-OH ++++ ++ Pal-LPR-OH ++++ +++ Myr-LPR-OH ++ Lau-LPR-OH +++H-LPR-OH =0 Pal-APR-OH +++ Pal-PPR-OH +++ ++ Pal-QPK-NH₂ ++ Pal-QPH-OH+++ Pal-QPM-OH +++ Pal-QPA-OH +++ ++ Pal-LPA-OH + ++ Myr-DPA-OH =0Pal-SPA-OH ++ Pal-PPA-OH + Pal-DPA-OH =0 Myr-SPA-OH ++ Pal-LGA-OH =0Pal-LPM-OH + Pal-IPM-OH + Pal-MPL-OH +++ Pal-PR-OH +++ + Myr-PR-OH +Pal-PM-OH +++ + Pal-PP-OH +++ Pal-PG-OH +++ Pal-PS-OH ++ Pal-PA-OH +++H-PA-OH =0 Pal-GA-OH =0 Pal-AP-OH ++ Pal-GP-OH +

The results show a more or less pro-pigmenting activity for arepresentative panel of peptides according to the invention.

The Table Gives Also Comparative Results:

The Pal-LGA-OH and Pal-GA-OH show no pro-pigmenting activity compared toPal-LPA-OH and Pal-PA-OH showing that when Proline is substituted by amore flexible amino acid, here glycine, it annihilates thepro-pigmenting activity.

It can also be seen that Myr-DPA-OH and Pal-DPA-OH, including an acidXaa₁ (Asp (D) aspartic acid) do not present either a pro-pigmentingactivity.

Furthermore, Pal-FPM-OH, with a nonpolar Xaa₁ (Phenylalanine Phe (F))does not present either a pro-pigmenting activity.

Finally, H-LPR-OH and H-PA-OH have no pro-pigmenting activity unlikePal-LPR and Pal-PA-OH respectively, which shows the importance of havingpeptides with a substitution at X or Y.

2. Pro-Pigmenting and Pro-Collagen Dual Activity

Normal human fibroblasts are seeded and placed in contact with thepeptides to test for 6 days in DMEMc +5% FCS. After the contact, thelayers are fixed and collagen 1 fibers are visualized by immunostainingwith a specific antibody. Quantification is then performed by imageanalysis. The positive control is TGF β10⁻⁶%.

Melanogenesis Melanogenesis on human Peptide on B16 cells melanocytesColl 1 Pal-SPR-OH ++++ ++ + Pal-PPR-OH +++ + Pal-QPA-OH +++ ++ +Pal-LPA-OH + ++ +++ Myr-SPA-OH ++ ++ Pal-PM-OH +++ + ++ Pal-PA-OH +++ ++

3. Activity on keratinocytes

Human keratinocytes are brought to just confluence in KSFMc environment.The contact with the actives and therefore their evaluation is then donein KSFMc medium alone or with calcium (0.8mm)*. Visual evaluation ofdifferentiation takes place after 2, 4/5 and 7 days of contact. *Calcium differentiation allows the creation of link structure betweenthe cells which leads to a better attachment of the basal layers.

Peptide Keratinocyte differenciation Pal-KT - positive control +++ at2.5 ppm Pal-LPR + at 10 ppm Pal-SPR + at 10 ppm Pal-PA + at 2 ppmPal-LPA ++ at 3 ppm

D) Galenics

Active Ingredient According to the Invention:

Formulas comprising a peptide of the invention either is in ahydrophobic excipient as in the previous examples or in a hydrophilicexcipient.

Different formulations are described below. Additional cosmetic activeingredients, in support and/or in complement of the activity of theactive ingredient according to the invention if necessary can be addedto the appropriate phase according to their hydrophobic or hydrophilicnature. These ingredients can be of any class according to their(s)function(s), place of application (body, face, neck, chest, hands, hair,eyelashes, eyebrows, body hair, etc.), final desired effect and targetconsumer, for example anti-aging, anti-wrinkle, moisturizing,anti-wrinkle, firming, anti-glycation, slimming, soothing, myo-relaxing,anti-redness, anti-stretch marks, etc. They are mentioned above in thetext.

1) Cream Form

Ingredient (INCI name) Weight % Phase A Sorbitan Stearate 3.00Cyclopentasiloxane (and) Cyclohexasiloxane 2.00 Ethylhexyl Palmitate3.00 Glyceryl Stearate (and) PEG-100 Stearate 3.00 EthylhexylMethoxycinnamate 1.00 Ethylhexyl Dimethyl PABA 1.00 Phase BDemineralised water Qsp 100 Ultrez 10 ™ (Carbomer) 0.40 Phase C Glycerin5.00 Conservatives qs Phase D Peptide according to the invention in afatty 2.00 excipient Phase E Potassium sorbate (Potassium Sorbate) 0.10Phase F Sodium hydroxyde 30% (Sodium Hydroxide) 0.60 Demineralised water6.00 Phase G Fragrance 0.10

Protocol:

Weigh phase A and heat to 75° C. in a water bath. Weigh phase B and letswell for 20 minutes. Melt phase C until dissolved and add to phase B.Heat phase (B+C) to 75° C. in a water bath. Pour phase A in phase (B+C)under stirring. Extemporaneously, add phase A to phase (A+B+C).Approximately at 45° C. add phase E and neutralize with phase F. Mixwell. At 35° C., add phase G. Homogenize well. pH: 6.20.

Examples of Ingredients that can be Added to this Formulation:

CALMOSENSINE™: soothing active for sensitive skins marketed by Sederma(WO1998/07744) comprising the Tyr-Arg lipo-dipeptide. It reducesdiscomfort feelings.

NG Birch Sap™: skin toning and moisturizing marketed by Sederma.

Shea Butter: having nourishing and protective properties for thetreatment of skin stressed by the environment.

2) Oil form, in particular for a spray

Ingredient (INCI name) Weight % Phase A Crodamol GTCC ™ (Capric/CaprylicTriglyceride) Qsp 100 Ethylhexyl Dimethyl PABA 2.00 EthylhexylMethoxycinnamate 2.00 Crodamol OS ™ (Ethylhexyl Stearate) 20.00Tocopherol Acetate 0.20 Phase B Peptide according to the invention in afatty 2.00 excipient Phase C Fragrance 0.05

Protocol:

Weigh phase A and put under helix stirring. Add phase B to phase A underhelix stirring. Mix well. Add phase C to phase (A+B).

Examples of Ingredients that can be Added to this Formulation:

REVIDRATE™: active marketed by Sederma (WO2011/086532) that inparticular improves the cohesion of the epidermis and its hydration.

RENOVAGE™: global anti-aging active ingredient marketed by Sederma(WO2006/120646).

Gel Form

Ingredient (INCI name) Weight % Phase A Demineralised water Qsp 100Ultrez 10 ™ (Carbomer) 0.20 Phase B PEG 400 ™ 5.00 Conservatives qsPhase C Dimethicone 4.00 Pemulen TR2 ™ (Acrylates/C10-30 Alkyl Acrylate0.20 Cross Polymer) Phase D Tween 20 ™ (Polysorbate 20) 1.00 Peptideaccording to the invention in a fatty 2.00 excipient Phase E Potassiumsorbate (Potassium Sorbate) 0.10 Phase F Sodium hydroxyde 30% (SodiumHydroxide) 0.60 Demineralised water 5.00 Phase G Fragrance 0.10

Protocol:

Disperse Ultrez 10 in water and let swell for 15 minutes. Heat phase Buntil dissolved and add to phase A. Weigh and mix phase C. Mix phase Dand add it to phase C; mix well. Add phase (C+D) to the phase (A+B).Then add phase E. Let swell for 1 hour. Mix well. Neutralize with phaseF. Finally, add phase G. pH: 6.10.

Examples of Ingredients that can be Added to this Formulation:

RESISTEM™: anti-aging marketed by Sederma (WO2012/104774), helping theskin to build its own anti-aging defense system, based on an extractobtained by cell culture of Globularia cordifolia plant.

AQUALANCE™: osmoprotector moisturising active ingredient marketed bySederma (WO2009/104118) comprising homarine and erythritol.

LEGANCE™: anti-aging active marketed by Sederma (WO2013/105047),corresponding to a Zingiber zerumbet smith extract obtained by CO₂supercritical in a water-soluble excipient and titrated in zerumboneingredient. It is a global anti-aging ingredient for legs. It improvestheir appearance and comfort by reducing water retention, improvingmicrocirculation and refining adipose tissue.

BODYFIT™: slimming/firming active ingredient comprising glaucinemarketed by Sederma (WO2004/024695). BODYFIT™ reduces the appearance ofcellulite and helps to improve drainage and water distribution in thetissues.

PRODIZIA™: active ingredient marketed by Sederma (WO2013/046137)fighting the signs cutaneous fatigue caused by glycation andglycoxidation.

JUVINITY™: active (WO2011/125039) marketed by Sederma reducing signs ofaging on the face and neckline, smoothing wrinkles, densifying andrestructuring the dermis.

Compact Powder Form

Ingredient (INCI name) Weight % Phase A Talc Qsp 100 Kaolin 2.00 CalciumStearate 1.00 Mica 4.00 Silica 1.00 Bismuth Oxychloride 2.00 PotassiumSorbate qs Phenoxyethanol qs Phase B Unipure ™ Black LC 989 HLC [CI77499 (and) 0.20 Hydrogenated Lecithin] Unipure ™ Red LC 381 HLC [CI77491 (and) 0.60 Hydrogenated Lecithin] Unipure ™ Yellow LC 182 HLC [CI77492 (and) 1.00 Hydrogenated Lecithin] Covapearl Star ™ Gold 2302 AS[CI 77891 (and) 0.50 CI 77491 (and) Synthetic Fluorphlogopite (and)Triethoxycaprylylsilane] Covapearl ™ Brown 838 HLC [CI 77491 (and) Mica1.00 (and) Hydrogenated Lecithin) Covapearl ™ Dark Blue 637 [CI 77510(&) 0.10 CI 77891 (&) Mica] Phase C Crodamol PTIS-LQ-(MV) ™[Pentaerythrityl 4.00 Tetraisostearate] Peptide according to theinvention in a fatty matrix 2.00 Phase D Fragrance 0.30

Protocol:

Weigh phase A and mix. Weigh phase B and pour into phase B. Pour (A+B)in the blender and mix. Add phase C to (A+B) in several times and mixeach time. Add phase D. Check homogeneity at each step.

Examples of ingredients that can be added to this formulation:

VEGESOME MOIST 24™: ingredient marketed by Sederma designed for theformulation of moisturizing powder makeup; it is a powder consisting ofhollow particles 25 microns (Lycopodium clavatum exins) loaded with anImperata cylindrica extract having moisturizing properties.

Other Cream Form

Ingredient (INCI name) Weight % Phase A Arlacel 170 ™ (Glyceryl Stearate(and) PEG-100 5.50 Stearate) Abil Wax 2434 ™ (Stearoxy Dimethicone) 3.00Acetulan ™ (Cetyl Acetate (and) Acetylated 1.50 Lanolin Alcohol)Crodacol C 90 ™ (Cetyl Alcohol) 1.50 Mineral Oil 3.00 Shea Butter 5.00Unsaponifiable Shea 1.00 Parsol MCX ™ (Ethylhexyl Methoxicinnamate) 3.50Phase B Demineralised water Qs 100 Phase C Carbopol 940 ™ (Carbomer)0.20 Phase D Demineralised water 2.00 Triethanolamine 99%(Triethanolamine) 0.20 Phase E Propylene Glycol 0.10 Mixed ParabensPhase F Sodium hydroxyde 30% (Sodium Hydroxide) 5.00 Demineralised waterqs Phase G Peptide according to the invention in an hydrophilic 2.00excipient

Protocol:

Weigh phase A and heat at 75° C. in a water bath. Weigh phase B and letswell for 20 minutes. Melt phase C until dissolved and add it to phaseB. Heat phase (B+C) at 75° C. in a water bath. Pour phase A in phase(B+C) under Staro stirring. Extemporaneously, add phase A to phase(A+B+C). At approximately 45° C. add phase E and neutralize with phaseF. Mix well. At 35° C., add phase G. Homogenize well. pH: 6.20.

Examples of Ingredients that can be Added to this Formulation:

SUBLISKIN™: active ingredient marketed by Sederma (WO2010/067327) thatmoisturizes and smooths the skin while allowing it to resist to externalaggressions.

VENUCEANE™: active marketed by Sederma (WO2002/066668) comprising aThermus thermophiles biotechnological extract, that prevents visiblesigns of photo-aging (spots, wrinkles, dryness . . . ), protects cellstructures from damages caused by UV and strengthens skin integrity.

MATRIXYL synthe'6™: peptide-based anti-wrinkle ingredient marketed bySederma (WO2010/082175) which helps repair skin damage caused by aging.

KOMBUCHKA™: active ingredient acting on complexion marketed by Sederma(WO2004/012650).

INTENSLIM™: slimming active ingredient marketed by Sederma(WO2013/105048) which is a synergistic combination of extracts obtainedby Globularia cordifolia plant cell culture, Zingiber zerumbet smithtitrated in zerumbone and vegetable caffeine obtained by supercriticalCO₂ extraction.

Repigmenting Hair Lotion

Ingredient (INCI name) Weight % Phase A Demineralised water Qsp 100Ethanol 50.00 Phase B Methyl Paraben 0.20 Butylene Glycol 2.00 Phase CTween 20 ™ [Polysorbate 20] 1.50 Fragrance 0.10 Phase D Peptideaccording to the invention 3.00

Protocol:

Weigh phase A. Weigh and melt phase B. Cool phase B. Mix phase B withphase A under propeller stirring. Mix phase C and add to phase (A+B).Add phase D to phase (A+B+C). pH: 6.70.

Examples of Ingredients that can be Added to this Formulation:

PROCAPIL™: anti-hair-loss active ingredient marketed by Sederma (WO00/58347) that combines a vitamin matrikine (biotinyl-GHK), apigenin (aflavonoid extracted from citrus) and oleanolic acid (root extract fromLoveyly hemsleya).

1. A dipeptide of formula (I):X-(Xaa1)n-Pro*-(Xaa2)m-Y  (I) wherein n=0 and m=1; Xaa2 is selected fromthe group consisting of Alanine (Ala, A) and Proline (Pro, P); whereinat the N terminal end of the dipeptide of formula (I), X is selectedfrom the group consisting of H, —CO—R1 and —SO2—R1; wherein at the Cterminal end of the tripeptide of formula (I), Y is selected from thegroup consisting of OH, OR1, NH2, NHR1 and NR1R2; wherein R1 and R2 areindependent from each other and selected from the group consisting of anacyl, alkyl, aryl, aralkyl, alkylaryl, alkoxy and aryloxy group, whereinsaid acyl, alkyl, aryl, aralkyl, alkylaryl, alkoxy and aryloxy group canbe linear, branched, cyclic, poly-cyclic, non-saturated, hydroxylated,carbonylated, phosphorylated and/or sulfured, and may include an O, Sand/or N heteroatom; wherein Pro* is Proline; and wherein the dipeptideof formula (I) does not include the dipeptide wherein X=H and Y=OH. 2.The dipeptide of formula (I) according to claim 1, wherein X is selectedfrom the group consisting of octanoyle (C₈), decanoyle (C₁₀), lauroyl(C₁₂), myristoyle (C₁₄), palmitoyle (C₁₆), stearoyle (C₁₈), biotinoyle,elaidoyle, oleoyle and lipoyle; more preferably selected from lauroyle(C₁₂), myristoyle (C₁₄) and palmitoyle (C₁₆).
 3. The dipeptide offormula (I) according to claim 1, wherein said dipeptide is X-PP-Y. 4.The dipeptide of formula (I) according to claim 3, wherein saiddipeptide is Pal-PP-OH.
 5. The dipeptide of formula (I) according toclaim 1, wherein said dipeptide is X-PA-Y.
 6. A dipeptide of formula(I):X-(Xaa1)n-Pro*-(Xaa2)m-Y  (I) wherein n=0 and m=1; Xaa2 is Alanine (Ala,A); wherein at the N terminal end of the dipeptide of formula (I), X isselected from the group consisting of H, —CO—R1 and —SO2—R1; wherein atthe C terminal end of the tripeptide of formula (I), Y is selected fromthe group consisting of OH, OR1, NH2, NHR1 and NR1R2; wherein R1 and R2are independent from each other and selected from the group consistingof an acyl, alkyl, aryl, aralkyl, alkylaryl, alkoxy and aryloxy group,wherein said acyl, alkyl, aryl, aralkyl, alkylaryl, alkoxy and aryloxygroup can be linear, branched, cyclic, poly-cyclic, non-saturated,hydroxylated, carbonylated, phosphorylated and/or sulfured, and mayinclude an O, S and/or N heteroatom; wherein Pro* is Proline; andwherein the dipeptide of formula (I) does not include the dipeptidewherein X=H and Y=OH
 7. The dipeptide of formula (I) according to claim6, wherein X is selected from the group consisting of octanoyle (C₈),decanoyle (C₁₀), lauroyl (C₁₂), myristoyle (C₁₄), palmitoyle (C₁₆),stearoyle (C₁₈), biotinoyle, elaidoyle, oleoyle and lipoyle; morepreferably selected from lauroyle (C₁₂), myristoyle (C₁₄) and palmitoyle(C₁₆).
 8. The dipeptide of formula (I) according to claim 6, whereinsaid dipeptide is Pal-PA-OH.
 9. A dipeptide of formula (I):X-(Xaa1)n-Pro*-(Xaa2)m-Y  (I) wherein n=0 and m=1; Xaa2 is Proline (Pro,P); wherein at the N terminal end of the dipeptide of formula (I), X isselected from the group consisting of H, —CO—R1 and —SO2—R1; wherein atthe C terminal end of the tripeptide of formula (I), Y is selected fromthe group consisting of OH, OR1, NH2, NHR1 and NR1R2; wherein R1 and R2are independent from each other and selected from the group consistingof an acyl, alkyl, aryl, aralkyl, alkylaryl, alkoxy and aryloxy group,wherein said acyl, alkyl, aryl, aralkyl, alkylaryl, alkoxy and aryloxygroup can be linear, branched, cyclic, poly-cyclic, non-saturated,hydroxylated, carbonylated, phosphorylated and/or sulfured, and mayinclude an O, S and/or N heteroatom; wherein Pro* is Proline; andwherein the dipeptide of formula (I) does not include the dipeptidewherein X=H and Y=OH.
 10. The dipeptide of formula (I) according toclaim 9, wherein X is selected from the group consisting of octanoyle(C₈), decanoyle (C₁₀), lauroyl (C₁₂), myristoyle (C14), palmitoyle(C₁₆), stearoyle (C₁₈), biotinoyle, elaidoyle, oleoyle and lipoyle; morepreferably selected from lauroyle (C₁₂), myristoyle (C₁₄) and palmitoyle(C₁₆).
 11. The dipeptide of formula (I) according to claim 9, whereinsaid dipeptide is Pal-PP-OH.